CN106279132A - 2,4-咪唑啉二酮杂环衍生物及其制备方法和用途 - Google Patents
2,4-咪唑啉二酮杂环衍生物及其制备方法和用途 Download PDFInfo
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- CN106279132A CN106279132A CN201510282844.4A CN201510282844A CN106279132A CN 106279132 A CN106279132 A CN 106279132A CN 201510282844 A CN201510282844 A CN 201510282844A CN 106279132 A CN106279132 A CN 106279132A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明属于化学医药领域,具体涉及2,4-咪唑啉二酮杂环衍生物及其制备方法和用途。本发明提供了一种2,4-咪唑啉二酮杂环衍生物,其结构如式Ⅰ所示。本发明还提供了上述2,4-咪唑啉二酮杂环衍生物的制备方法和用途。本发明提供的2,4-咪唑啉二酮杂环衍生物对Pim-1蛋白激酶小分子有较好的抑制作用,具有重要的开发应用前景。
Description
技术领域
本发明属于化学医药领域,具体涉及2,4-咪唑啉二酮杂环衍生物及其制备方法和用途。
背景技术
Pim-1是丝氨酸/苏氨酸激酶Pim家族中的一种。Pim-1基因最早是作为莫洛尼小鼠白血病病毒的前病毒插入点而被发现的。Pim-1作为一种原癌基因,在白血病、淋巴瘤以及前列腺癌的形成过程中均发现Pim-1过度表达。Pim-1基因高表达可抑制肿瘤细胞凋亡,促进肿瘤细胞增殖并阻滞细胞分化成熟,在肿瘤的发生发展过程中起重要作用。Pim-1激酶通过多种机制影响肿瘤细胞的增殖和存活:Pim-1激酶与转录因子协同作用,促进肿瘤细胞增殖;Pim-1激酶也可通过磷酸化凋亡蛋白BAD和ASK1来增加细胞存活;Pim-1激酶通过调节多种细胞周期因子来调节细胞周期,诱导细胞的增殖。Pim-1激酶通过调节细胞信号通路,增强细胞存活能力。由于Pim-1蛋白激酶在肿瘤发生、发展中扮演重要角色,Pim-1蛋白激酶将成为抗肿瘤药物的重要靶标。发展新型Pim-1蛋白激酶抑制剂作为抗肿瘤药物具有良好的应用前景。
目前,临床上应用的抗肿瘤药物种类繁多,其中化疗药物主要有烷化剂钼络合物抗肿瘤药物、蒽环类抗肿瘤药物、破坏DNA的抗生素等。此外,天然抗肿瘤药物的研究也占有相当大的比例,如目前临床上常用一些药物有喜树碱、长春新碱、紫杉醇等。
然而,现有的抗肿瘤药物存在着选择性较差、毒副作用、耐药性等问题。寻找高效低毒的抗肿瘤药物仍是科学家面临的重要课题。
发明内容
本发明提供了一种2,4-咪唑啉二酮杂环衍生物,其结构如式Ⅰ所示:
其中,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;
R1为-H、C1~C4烷基、卤素、C1~C4烷氧基、
R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;
R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
R5为-COOH、苯基、C3~C8环烷基或卤素。
作为本发明优选的方案,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1~4;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
进一步优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
更进一步优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
最优的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH或苯基。
上述2,4-咪唑啉二酮杂环衍生物,当Y1为N、O或S,Y2、Y3和Y4为C时,其结构如式Ⅱ所示:
其中,X1、X2独立地为O或S;
R1为-H、C1~C4烷基、卤素、C1~C4烷氧基、
R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;
R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
R5为-COOH、苯基、C3~C8环烷基或卤素。
作为优选的方案,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1~4;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
进一步优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
更进一步优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3或-NH2;R5为-COOH、苯基、C3~C8环烷基或卤素。
最优的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3或-NH2;R5为-COOH或苯基。
上述2,4-咪唑啉二酮杂环衍生物,当Y2为N、O或S,Y1、Y3和Y4为C时,其结构如Ⅲ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH。
进一步优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基。
最优的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H。
上述2,4-咪唑啉二酮杂环衍生物,当Y1和Y2为N,Y3和Y4为C时,其结构如式Ⅳ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH。
进一步优选的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H或C1~C4烷基。
最优的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H。
上述2,4-咪唑啉二酮杂环衍生物,当Y1为N、O或S,Y3为N,Y2和Y4为C时,其结构如式Ⅴ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
进一步优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H、C1~C4烷基、卤素或C1~C4烷氧基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH。
更进一步优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H;R4为-H、C1~C4烷基或-OH。
最优的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H;R4为-H或-OH。
上述2,4-咪唑啉二酮杂环衍生物,当Y1为N或S,Y2和Y3为C,Y4为N时,其结构如式Ⅵ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH。
进一步优选的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H或C1~C4烷基。
最优的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H。
上述2,4-咪唑啉二酮杂环衍生物,其结构式为:
本发明还提供了上述2,4-咪唑啉二酮杂环衍生物的制备方法,合成路线如下:
其中,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、卤素、C1~C4烷氧基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素。
上述2,4-咪唑啉二酮杂环衍生物的制备方法,包括以下步骤:将咪唑啉二酮原料、杂环甲醛和哌啶在乙醇中回流反应24h,然后加入少量水,再用乙酸酸化,得到粗产品,最后经重结晶或柱层析纯化后得式Ⅰ化合物。
其中,上述2,4-咪唑啉二酮杂环衍生物的制备方法,所述咪唑啉二酮原料、杂环甲醛和哌啶的摩尔比为1︰1︰0.8。
本发明还提供了上述2,4-咪唑啉二酮杂环衍生物药学上可接受的盐或水合物。
一种药物组合物,是由式Ⅰ~式Ⅵ所示的2,4-咪唑啉二酮杂环衍生物及其盐或水合物添加药学上可以接受的辅助性成分制备而成的。
本发明还提供了上述式Ⅰ~式Ⅵ所示的2,4-咪唑啉二酮杂环衍生物及其盐或水合物在制备Pim-1蛋白激酶小分子抑制剂中的用途。
本发明还提供了上述式Ⅰ~式Ⅵ所示的2,4-咪唑啉二酮杂环衍生物及其盐或水合物在制备抗肿瘤药物中的用途。
本发明提供的2,4-咪唑啉二酮杂环衍生物对Pim-1蛋白激酶小分子有较好的抑制作用,具有重要的开发应用前景。
具体实施方式
2,4-咪唑啉二酮杂环衍生物的制备方法,包括以下步骤:将咪唑啉二酮原料、杂环甲醛和哌啶在乙醇中回流反应24h,然后加入少量水,再用乙酸酸化,得到粗产品,最后经重结晶或柱层析纯化后得式Ⅰ化合物。
其中,上述2,4-咪唑啉二酮杂环衍生物的制备方法,所述咪唑啉二酮原料、杂环甲醛和哌啶的摩尔比为1︰1︰0.8。
实施例1 5-((2-噻吩)-2-乙烯基)-咪唑啉-2,4-二酮(化合物1)的合成
称取2,4-咪唑啉二酮20mmol,2-噻吩甲醛20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(乙醇)150mL溶解,混合液回流反应24h。然后加入少量水,用乙酸酸化后得到粗产品,甲醇重结晶后得得到化合物1,收率50%。
1H NMR(400MHz,CDCl3)δ6.04(s,1H),6.52(s,1H),7.50-7.55(m,1H),7.70-7.74(m,1H),8.10-8.13(m,1H),10.03(s,1H)。
实施例2 化合物2~39的合成
采用与实施例1相同的操作步骤,以相应原料与2,4-咪唑啉二酮反应,制备得到化合物2~39。
化合物2~39的结构式、中文名称及其分子量见表1所示。
表1 化合物2~39的结构式、中文名称及其分子量
实施例3 5-((2-呋喃)-2-乙烯基)-3-甲基-咪唑啉-2,4-二酮(化合物40)的合成
将2,4-咪唑啉二酮(1.0equiv)溶解于40mL甲苯中,加入N,N-dimethylacetamide dimethylacetal(N,N-二甲基乙酰胺二甲基缩醛)(3.0equiv),反应液110℃搅拌2h后冷却到室温在冷却到0℃15min。过滤得到滤渣,滤渣用甲苯洗5次后真空干燥后得3-methylimidazolidine-2,4-dione(3-甲基-咪唑啉-2,4-二酮)。收率50%。
1H NMR(400MHz,CDCl3)δ3.04(s,3H),3.99(s,2H),6.09(s,1H)。
称取3-methylimidazolidine-2,4-dione(3-甲基-咪唑啉-2,4-二酮)20mmol,2-呋喃甲醛20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物40,收率45%。
1H NMR(400MHz,CDCl3)δ3.05(s,3H),6.04(s,1H),6.54(s,1H),6.85-6.89(m,1H),7.66-7.70(m,1H),8.14-8.17(m,1H)。
实施例4 5-((2-呋喃)-2-乙烯基)-1,3-二甲基-咪唑啉-2,4-二酮(化合物41)的合成
在2,4-咪唑啉二酮(1.0equiv)和K2CO3(3.0equiv)的干燥DMF(N,N-二甲基甲酰胺)5mL溶液中加入MeI(碘甲烷3equiv),在60℃搅拌反应12h。然后加入水后中止反应,混合液用乙酸乙酯萃取3次,有机相用盐水洗,无水Na2SO4干燥,过滤浓缩后柱层析纯化得1,3-Dimethylimidazolidine-2,4-dione(1,3-二甲基-咪唑啉-2,4-二酮),收率54%。
1H NMR(400MHz,CDCl3)δ2.87(3H,s),2.87(3H,s),3.76(2H,s);13C NMR(100MHz,CDCl3)δ24.7,29.5,51.6,157.0,170.0。HRMS(ESI):129.0664[M+H]+。
称取1,3-Dimethylimidazolidine-2,4-dione(1,3-二甲基-咪唑啉-2,4-二酮)20mmol,2-呋喃甲醛20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物41,收率35%。
1H NMR(400MHz,CDCl3)δ3.16(s,3H),3.32(s,3H),6.55(s,1H),6.81-6.83(m,1H),7.64-7.68(m,1H),8.13-8.17(m,1H)。
实施例5:5-((2-呋喃)-2-乙烯基)-3-苄基-咪唑啉-2,4-二酮(化合物42)的合成
2,4-咪唑啉二酮(1.0equiv)、苄溴(1.0equiv)、氢化钠(1.1equiv)在DMF(20mL)中室温反应18h,反应液用水稀释后用乙酸乙酯萃取,有机相水洗6次后无水硫酸钠干燥。丙酮、正己烷重结晶后得3-benzylimidazolidine-2,4-dione(3-苄基-咪唑啉-2,4-二酮),收率40%。
1H NMR(400MHz,CDCl3)δ3.97(s,2H),4.67(s,2H),5.78(s,1H),6.85-7.70(m,5H);13CNMR(100MHz,CDCl3)δ41.0,46.0,127.3,127.4,128.4,136.8,157.3,171.9。HRMS(m/z):191.0815[M+H]+。
称取3-benzylimidazolidine-2,4-dione(3-苄基-咪唑啉-2,4-二酮)20mmol,2-呋喃甲醛20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物42,收率35%。
1H NMR(400MHz,CDCl3)δ5.20(s,2H),6.02(s,1H),6.52(s,1H),6.81-6.83(m,1H),7.23-7.27(m,5H),7.64-7.68(m,1H),8.13-8.17(m,1H)。
实施例6 化合物43(5-((2-呋喃)-2-乙烯基)-3-异丙基-咪唑啉-2,4-二酮)的合成
按照实施例5的操作步骤,以2-溴丙烷为原料与2,4-咪唑啉二酮反应,制备得到化合物43。收率41%,分子量:220。
实施例7 5-((2-呋喃)-2-乙烯基)-3-羧乙基-咪唑啉-2,4-二酮(化合物44)的合成
将2,4-咪唑啉二酮(1.0equiv)溶于5mL乙醇(EtOH)中,加入KOH(1.2equiv)的乙醇溶液。混合液于70℃搅拌1h后冰浴冷却,生成白色固体,过滤后,沉淀用乙醇洗涤,干燥后可得产物potassium 2,5-dioxoimidazolidin-1-ide(2,4-咪唑啉二酮钾盐)。
将potassium 2,5-dioxoimidazolidin-1-ide(2,4-咪唑啉二酮钾盐)(1.0.equiv)和KI(1.4equiv)溶于10mL无水DMF,缓慢加入溴乙酸叔丁酯(1.0equiv)。混合液在95℃搅拌4h。冷却至室温后,加入50mL水。加入乙醚萃取。有机相用饱和NaHCO3,盐水洗涤,无水Na2SO4干燥。蒸干溶剂后残留物柱层析得到N上取代产物N-Boc-2,4-咪唑啉二酮。
将2-呋喃甲醛(1.0equiv),N-Boc-2,4-咪唑啉二酮(1.0equiv)和哌啶(3.0equiv)称入圆底烧瓶,加入150mL乙醇溶解。混合液回流24h后加入水,然后加入乙酸酸化,生成沉淀。过滤,用无水乙醇洗涤沉淀得产物tert-butyl2-(4-(furan-2-ylmethylene)-2,5-dioxoimidazolidin-1-yl)acetate((5-((2-呋喃)-2-乙烯基)--3-N-Boc)-咪唑啉-2,4-二酮)。
将tert-butyl 2-(4-(furan-2-ylmethylene)-2,5-dioxoimidazolidin-1-yl)acetate(5-((2-呋喃)-2-乙烯基)-3-N-Boc)-咪唑啉-2,4-二酮)加入圆底烧瓶中,加入二氯甲烷溶解,滴加TFA,反应2h,蒸干TFA(三氟乙酸)和二氯甲烷,在残留物中加入乙酸乙酯生成固体,过滤并用乙酸乙酯多次洗涤,最后烘干后得到化合物44。
1H NMR(400MHz,CDCl3)δ4.46(s,2H),6.00(s,1H),6.55(s,1H),6.80-6.82(m,1H),7.64-7.66(m,1H),8.14-8.17(m,1H),10.89(s,1H)。
实施例8 5-((2-呋喃)-2-乙烯基)-3-乙基-咪唑啉-2,4-二酮(化合物45)的合成
按照实施例5的操作步骤,以溴乙烷为原料与2,4-咪唑啉二酮反应,制备得到化合物45。收率42%,分子量:206。
实施例9 5-((2-(5-苯基噻吩)-2-乙烯基)-咪唑啉-2,4-二酮(化合物46)的合成
将5-bromo-thiophene-2-carbaldehyde(5-溴噻吩-2-甲醛)(1.0equiv)和phenylboronic acid(苯硼酸)(2.0equiv)溶解于20mL甲苯,20mL乙醇和5mL 2N的Na2CO3混合溶液中,反应体系脱氧三次后,加入5mol%的Pd(PPh3)4(四三苯基磷钯),反应液加热回流4h,冷却后,过滤固体,水相用乙酸乙酯萃取2次,有机相合并后无水硫酸钠干燥,浓缩后柱层析纯化得5-phenylthiophene-2-carbaldehyde(5-苯基噻吩-2-甲醛),收率99%。
1H NMR(CDCl3,400MHz):δ7.32-7.38(m,4H),7.59-7.61(m,2H),7.67(d,J=3.8Hz,1H),9.82(s,1H)。13C NMR(CDCl3,100MHz):δ123.1,125.4,128.2,128.4,132.1,136.3,141.5,153.3,181.8。MS(ESI):m/z=189.0[M+H]+。
称取2,4-咪唑啉二酮20mmol,5-phenylthiophene-2-carbaldehyde(5-苯基噻吩-2-甲醛)20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,柱层析纯化得到化合物46,收率40%。
1H NMR(CDCl3,400MHz):δ5.89(s,1H),6.55(s,1H),7.41-7.51(m,3H),7.75-7.79(m,2H),8.00-8.05(m,1H),8.20-8.24(m,1H),10.42(s,1H)。
实施例10 化合物47~51的合成
采用与实施例9相同的操作步骤,制备得到化合物47~51。
化合物47~51的结构式、中文名称及其分子量见表1所示。
表1 化合物47~51的结构式、中文名称及其分子量
实施例11 5-(2-(5-苯基-吡咯)-2-乙烯基)-咪唑啉-2,4-二酮(化合物52)的合成
在NaH(1.0equiv)的THF溶液中,5℃时滴加diethyl(2-oxo-2-phenylethyl)phosphonate(二乙基(2-氧代-2-苯乙基)膦酸)(1.0equiv)。反应液室温搅拌半小时。室温滴加oxazole-4-carbaldehyde(恶唑-4-甲醛)(1.0equiv)的THF溶液。反应液室温搅拌半小时,加入2N的HCl酸化,乙酸乙酯萃取,有机相合并后无水硫酸钠干燥,浓缩后柱层析纯化得3-(oxazol-4-yl)-1-phenylprop-2-en-1-one(3-(4-恶唑基)-1-苯基-2-丙烯-1-酮,收率:80%。
1H NMR(400MHz,DMSO)δ7.56-7.60(m,2H),7.66(d,J=15.6Hz,1H),7.66-7.70(m,1H),7.74(d,J=15.6Hz,1H),8.03-8.05(m,2H),8.56(s,1H),8.50(s,1H)。13C NMR(100MHz,DMSO-d6)δ122.7,128.3,128.9,132.5,133.2,136.4,137.3,141.9,153.1,189.1。HRMS(ESI)200.0706[M+H]+。
将3-(oxazol-4-yl)-1-phenylprop-2-en-1-one(3-(4-恶唑基)-1-苯基-2-丙烯-1-酮,1.0equiv)溶解于6.0mLTHF中,室温下加入6.0mL 2N的NaOH溶液。反应液70℃搅拌14h,冷却到室温,用盐水稀释后,乙酸乙酯萃取,有机相浓缩后柱层析纯化得5-phenyl-1H-pyrrole-2-carbaldehyde(5-苯基-1H-吡咯-2-甲醛),收率:80%。
1H NMR(400MHz,DMSO)δ6.79(d,J=4.0Hz,1H),7.08(d,J=4.0Hz,1H),7.30-7.34(m,1H),7.40-7.44(m,2H),7.88-7.91(m,2H),9.49(s,1H),12.41(s,1H)。13C NMR(100MHz,DMSO-d6)δ108.9,121.9,125.5,128.0,128.8,130.8,133.8,139.5,178.8。HRMS(ESI)172.0756[M+H]+。
称取2,4-咪唑啉二酮20mmol,5-phenyl-1H-pyrrole-2-carbaldehyde(5-苯基-1H-吡咯-2-甲醛)20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物52,收率40%。
1H NMR(400MHz,CDCl3)δ6.02(s,1H),6.54(s,1H),6.75(d,J=4.0Hz,1H),7.05(d,J=4.0Hz,1H),7.31-7.35(m,1H),7.40-7.47(m,2H),7.89-7.92(m,2H),9.49(s,1H),10.41(s,1H)。
实施例12 化合物53、54的合成
采用与实施例11相同的操作步骤,制备得到化合物53、54。
化合物53、54的结构式、中文名称及其分子量见表1所示。
表1 化合物53、54的结构式、中文名称及其分子量
实施例13 5-(2-(5-苯基-恶唑)-2-乙烯基)-咪唑啉-2,4-二酮(化合物55)的合成
propargylamide(炔丙基苯酰胺)1.0equiv和NIS(N-碘代二酰亚胺)1.2equiv溶解于4mL现置的干燥二氯甲烷中。反应液室温搅拌2h后加入硫代硫酸钠。用乙醚萃取有机相,合并有机相后用盐水洗,无水MgSO4,干燥过滤,浓缩后柱层析纯化后得(E)-5-(Iodomethylene)-2-phenyl-4,5-dihydrooxazole((E)-5-(碘代甲基)-2-苯基-4,5-二氢恶唑),收率:90%。
1H NMR(400MHz,CDCl3):δ4.63(d,J=3.2Hz,2H),5.78(t,J=3.2Hz,1H),7.45(t,J=7.6Hz,2H),7.53(t,J=7.6Hz,1H),7.86-8.04(m,2H)。13C NMR(100MHz,CDCl3):δ47.0,61.0,126.3,127.8,128.4,131.9,157.8,163.8。
将(E)-5-(Iodomethylene)-2-phenyl-4,5-dihydrooxazoler(E)-5-(碘代甲基)-2-苯基-4,5-二氢恶唑)0.2mmol溶解于2mL二氯甲烷溶液中,在O2氛围下80℃搅拌,TLC监测反应过程,反应完成后蒸发溶剂,柱层析纯化得2-Phenyloxazole-5-carbaldehyde(2-苯基恶唑-5-甲醛),收率:80%。
1H NMR(400MHz,CDCl3):δ7.47-7.57(m,3H),7.96(s,1H),8.18(d,J=7.2Hz,2H),9.82(s,1H)。13C NMR(100MHz,CDCl3):δ126.0,127.8,129.2,132.4,139.2,149.7,165.6,176.4。HRMS(ESI-TOF)m/z:174.0555[M+H]+。
称取2,4-咪唑啉二酮20mmol,2-Phenyloxazole-5-carbaldehyde(2-苯基恶唑-5-甲醛)20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物55,收率35%。
1H NMR(400MHz,CDCl3)δ6.01(s,1H),6.55(s,1H),7.41-7.47(m,3H),7.92(s,1H),8.08(d,J=7.2Hz,2H),10.03(s,1H)。
实施例14 5-((2-(5-间羟基苯基-恶唑)-2-乙烯基-)咪唑啉-2,4-二酮(化合物56)的合成
按照实施例13的操作步骤,以2-间羟基苯基恶唑-5-甲醛为原料与2,4-咪唑啉二酮反应,制备得到化合物56。收率40%,分子量:271。
实施例15 5-((2-(5-苯基-噻唑)-2-乙烯基-)咪唑啉-2,4-二酮(化合物57)的合成
thiobenzamide(硫代苯甲酰胺)(1.0equiv)、5-溴噻吩-2甲醛(1.0equiv)和2-chloromalonedialdehyde(2-氯丙二醛)溶解于丙酮中回流反应2h。反应完成后加入水稀释,用乙酸乙酯萃取,合并有机相无水硫酸钠干燥过滤,浓缩后柱层析纯化得2-phenylthiazole-5-carbaldehyde(2-苯基噻唑-5-甲醛)。
称取2,4-咪唑啉二酮20mmol,2-Phenylthiazole-5-carbaldehyde(2-苯基噻唑-5-甲醛)20mmol,哌啶16mmol于圆底烧瓶中,用EtOH(150mL)溶解,混合液回流24h。加入少量水,用乙酸酸化后得粗产品,甲醇重结晶后得到化合物57,收率41%。
1H NMR(400MHz,CDCl3)δ6.02(s,1H),6.52(s,1H),7.42-7.51(m,3H),8.00-8.04(m,2H),8.60(s,1H),10.04(s,1H)。
实施例16 本发明化合物的激酶抑制活性检测
本实验的目的是检测所发明化合物对体外激酶的抑制活性,采用的方法为同位素标记法。本实验分别对3种激酶进行体外活性测试,包括PIM-1、PIM-2、PIM-3。受试化合物的激酶抑制活性用IC50来表示。
PIM1、PIM2和PIM3均购于美国Millipore Corporation公司。
1)试验方法:
在384孔V型底的聚丙烯板中,加入10μL不同浓度的目标化合物(100μM,30μM,10μM,3μM,1μM,0.3μM,0.1μM,0.01μM,0.001μM),再依次加入①20μL人重组PIM1(50pM)[或PIM2(500pM),或PIM3(300pM)],②底物肽(biotin-C6linker-VRRLRRLTAREAA)(20μM),③20μL λ-[33P]-ATP(5μM,2mCi/μmol),缓冲液25mM HEPES(4-羟乙基哌嗪乙磺酸),pH 7.4,0.5mM DTT(二硫苏糖醇),10mM MgCl2,100μM Na3VO4,0.075mg/mL Triton X-100(聚乙二醇辛基苯基醚)。室温下培养1h,轻振下加入60μL缓冲液(50mM EDTA(乙二胺四乙酸),2M NaCl)。转入链霉亲和素涂覆的384孔V型底的聚丙烯板中,室温孵化30min,用0.05%吐温20的PBS(磷酸缓冲溶液)溶液洗三次后,在液闪读数仪(Wallac MicroBeta Trilux,Turku,Finland)定量测定放射性PtdIns(3)P,计算IC50值。
2)实验结果:
表1 本发明化合物对激酶的IC50(uM)
化合物 | PIM-1 | PIM-2 | PIM-3 |
1 | 1.8 | 56 | 78 |
2 | 1.7 | 45 | 65 |
3 | 2.6 | 34 | 21 |
4 | 1.3 | 26 | 31 |
5 | 1.2 | 46 | 22 |
6 | 2.8 | 21 | 12 |
7 | 0.6 | 23 | 14 |
8 | 3.6 | 32 | 54 |
9 | 2.6 | 12 | 27 |
10 | 8.1 | 34 | 47 |
11 | 7.9 | 29 | 56 |
12 | 8.0 | 21 | 16 |
13 | 6.8 | 39 | 19 |
14 | 0.3 | 12 | 32 |
15 | 6.3 | 64 | 29 |
16 | 6.9 | 33 | 25 |
17 | 7.4 | 21 | 24 |
18 | 13.2 | 15 | 47 |
19 | 11.8 | 28 | 46 |
20 | 17.9 | 32 | 16 |
21 | 7.4 | 25 | 28 |
22 | 9.6 | 15 | 68 |
23 | 13.2 | 14 | 21 |
24 | 15.3 | 27 | 15 |
25 | 2.9 | 18 | 43 |
26 | 18 | 21 | 27 |
27 | 7.9 | 35 | 24 |
28 | 3.8 | 28 | 31 |
29 | 12 | 29 | 25 |
30 | 9 | 30 | 20 |
31 | 8.9 | 17 | 22 |
32 | 7.9 | 20 | 30 |
33 | 8.8 | 18 | 22 |
34 | 6.7 | 22 | 38 |
35 | 12 | 24 | 33 |
36 | 8.1 | 28 | 24 |
37 | 9.2 | 42 | 39 |
38 | 5.5 | 64 | 31 |
39 | 17 | 22 | 28 |
40 | 4.9 | 21 | 42 |
41 | 3.8 | 55 | 61 |
42 | 14 | 32 | 19 |
43 | 4.7 | 36 | 25 |
44 | 8.3 | 46 | 51 |
45 | 6.1 | 36 | 54 |
46 | 4.6 | 63 | 48 |
47 | 8.3 | 53 | 45 |
48 | 5.7 | 43 | 54 |
49 | 8.8 | 62 | 85 |
50 | 9.6 | 32 | 44 |
51 | 12 | 66 | 36 |
52 | 14 | 42 | 75 |
53 | 8.4 | 43 | 36 |
54 | 4.9 | 46 | 74 |
55 | 5.7 | 55 | 47 |
56 | 6.3 | 78 | 68 |
57 | 8.2 | 66 | 54 |
表1中的实验结果表明,化合物1~57对Pim-1激酶具有明显的抑制活性。所有化合物对PIM-1激酶的活性抑制IC50<20uM。实施例中的化合物对PIM-2,Pim-3激酶的活性也有相当的抑制作用。
实施例17 Pim-1蛋白激酶小分子抑制剂的体外肿瘤细胞增殖抑制实验
本发明的抑制Pim-1蛋白激酶的小分子是一类高效低毒的抗肿瘤活性化合物,对多种恶性肿瘤有明显疗效。
A549为人肺腺癌细胞,购买于American Type Culture Collection(ATCC,Rockville,MD,USA)。
B16为黑色素瘤细胞,购买于American Type Culture Collection(ATCC,Rockville,MD,USA)。
PC-3为前列腺癌细胞,购买于American Type Culture Collection(ATCC,Rockville,MD,USA)。
DU145为前列腺癌细胞,购买于American Type Culture Collection(ATCC,Rockville,MD,USA)。
细胞培养用胎牛血清购杭州四季青生物工程公司
1)试验方法:
用一组肿瘤细胞系,即A549,B16,PC-3,DU145来检测上述小分子的体外抗肿瘤活性。
A549,B16,PC-3,DU145细胞用5%胎牛血清的RPIM1640培养基(含100U/mL青霉素,100U/mL链霉素)。在含5%CO2:(v/v)饱和湿度培养箱中37℃培养。当培养至7-8成满的时候,用消化液消化细胞,1000rpm离心富集细胞,PBS洗涤一次后按照1/6每瓶分瓶培养于新的细胞培养瓶中,继续培养。取对数期的生长状态良好的细胞进行试验操作。
在96孔板中接种最终密度为10000个细胞/mL的肿瘤细胞。利用试验化合物处理细胞(至少5个不同浓度),每浓度均作6个平行孔,另设空白孔和对照孔,药物作用期间,用倒置相差显微镜观察细胞的生长情况,在37℃ CO2培养箱中培养72小时后,每孔加入5g/L的MTT(四唑溴盐)20μL,培养4h,弃上清液,加DMSO(二甲基亚砜)约100μL/孔,振荡10min,使紫色结晶物充分溶解,用酶标仪测定490nm处的吸光度。根据IC50的值表示试验化合物的细胞毒性。上述值表示6个平行样的平均值。
2)实验结果:
表2 本发明化合物对肿瘤细胞增殖的抑制作用
化合物 | A549 | B16 | PC-3 | DU145 |
1 | 13.9 | 25.3 | 67.9 | 21.8 |
2 | 21.6 | 4.8 | 56.8 | 33.0 |
3 | 4.9 | 32.9 | 23.1 | 44.8 |
4 | 34.2 | 46.2 | 34.9 | 21.9 |
5 | 18.5 | 12.7 | 14.9 | 15.3 |
6 | 22.1 | 13.8 | 8.5 | 18.5 |
7 | 0.8 | 24.8 | 11.7 | 1.2 |
8 | 12.1 | 17.5 | 21.7 | 29.5 |
9 | 12.9 | 32.7 | 21.9 | 46.2 |
10 | 7.9 | 29.5 | 12.3 | 44.8 |
11 | 23.8 | 19.3 | 14.6 | 33.6 |
12 | 6.8 | 13.2 | 12.7 | 43.9 |
13 | 22.6 | 46.3 | 25.3 | 24.8 |
14 | 0.6 | 13.7 | 2.7 | 22.8 |
15 | 18.5 | 5.8 | 25.1 | 13.3 |
16 | 14.5 | 11.4 | 15.6 | 17.4 |
17 | 13.2 | 21.8 | 23.5 | 11.5 |
18 | 3.8 | 11.9 | 27.7 | 14.6 |
19 | 9.6 | 7.2 | 24.2 | 13.8 |
20 | 14.5 | 13.3 | 35.2 | 15.7 |
21 | 21.8 | 21.5 | 25.6 | 32.1 |
22 | 5.8 | 4.6 | 13.6 | 16.4 |
23 | 8.8 | 13.3 | 16.4 | 21.5 |
24 | 6.9 | 7.8 | 13.2 | 15.5 |
25 | 13.6 | 7.9 | 12.7 | 32.8 |
26 | 23.8 | 22.6 | 12.9 | 12.5 |
27 | 16.9 | 13.2 | 15.4 | 17.5 |
28 | 25.4 | 2.9 | 2.4 | 8.6 |
29 | 15.7 | 17.8 | 41.3 | 26.1 |
30 | 9.5 | 6.3 | 15.8 | 26.9 |
31 | 3.8 | 13.2 | 28.4 | 15.9 |
32 | 0.9 | 1.2 | 8.8 | 7.6 |
33 | 25.7 | 16.2 | 12.5 | 15.3 |
34 | 16.4 | 23.5 | 27.2 | 13.1 |
35 | 11.4 | 0.5 | 23.5 | 27.1 |
36 | 7.4 | 9.3 | 12.4 | 13.2 |
37 | 5.8 | 7.6 | 24.8 | 25.1 |
38 | 48.1 | 32.6 | 54.2 | 22.6 |
39 | 5.5 | 7.8 | 0.4 | 21.7 |
40 | 22.6 | 21.6 | 32.4 | 7.5 |
41 | 13.7 | 23.1 | 9.3 | 8.4 |
42 | 14.7 | 22.4 | 7.6 | 6.3 |
43 | 11.5 | 6.5 | 12.5 | 8.4 |
44 | 12.4 | 23.5 | 28.6 | 29.7 |
45 | 22.4 | 21.6 | 13.5 | 17.6 |
46 | 14.7 | 8.4 | 22.6 | 5.3 |
47 | 24.5 | 21.5 | 5.9 | 32.7 |
48 | 3.7 | 0.7 | 12.0 | 20.5 |
49 | 4.8 | 18.5 | 16.7 | 22.4 |
50 | 5.2 | 20.8 | 13.1 | 12.9 |
51 | 9.8 | 13.2 | 31.2 | 25.1 |
52 | 10.3 | 15.3 | 17.2 | 22.0 |
53 | 13.2 | 6.6 | 11.1 | 17.2 |
54 | 8.8 | 12.4 | 7.4 | 8.8 |
55 | 6.8 | 12.7 | 7.5 | 8.6 |
56 | 5.8 | 6.6 | 12.4 | 15.8 |
57 | 6.5 | 0.7 | 6.8 | 6.9 |
结果表明,在上述测试的化合物1~57都有效地抑制了A549,B16,PC-3,DU145细胞的生长。出乎意料的是,它们中大多数都表示出的IC50值小于1mM,一些甚至小于100nM。其中,化合物7、14、32对A549细胞的IC50<1.0μM,化合物35、48、57对B16细胞的IC50<1.0μM,化合物39对PC-3细胞的IC50<1.0μM。
同时,本发明提供的化合物在安全性、稳定性、溶解性等方面也可能存在一定的优势。
Claims (13)
1.2,4-咪唑啉二酮杂环衍生物,其结构如式Ⅰ所示:
其中,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;
R1为-H、C1~C4烷基、卤素、C1~C4烷氧基、
R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;
R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
R5为-COOH、苯基、C3~C8环烷基或卤素。
2.根据权利要求1所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:
X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1~4;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
进一步优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
更进一步优选的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
最优的,X1、X2独立地为O或S;Y1、Y2、Y3、Y4独立地为C、N、O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH或苯基。
3.权利要求1或2所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:当Y1为N、O或S,Y2、Y3和Y4为C时,其结构如式Ⅱ所示:
其中,X1、X2独立地为O或S;
R1为-H、C1~C4烷基、卤素、C1~C4烷氧基、
R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;
R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
R5为-COOH、苯基、C3~C8环烷基或卤素。
4.根据权利要求3所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:
X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1~4;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
进一步优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
更进一步优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3或-NH2;R5为-COOH、苯基、C3~C8环烷基或卤素;
最优的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H、C1~C4烷基或n=1或2;R4为-H、C1~C4烷基、C1~C4烷氧基、-CF3或-NH2;R5为-COOH或苯基。
5.权利要求1或2所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:当Y2为N、O或S,Y1、Y3和Y4为C时,其结构如Ⅲ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;R1为-H、R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
进一步优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基;
最优的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H。
6.权利要求1或2所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:当Y1和Y2为N,Y3和Y4为C时,其结构如式Ⅳ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
进一步优选的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H或C1~C4烷基;
最优的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H。
7.权利要求1或2所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:当Y1为N、O或S,Y3为N,Y2和Y4为C时,其结构如式Ⅴ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
进一步优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H、C1~C4烷基、卤素或C1~C4烷氧基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
更进一步优选的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H;R4为-H、C1~C4烷基或-OH;
最优的,X1、X2独立地为O或S;R1为-H、C1~C4烷基或R2、R3独立地为-H;R4为-H或-OH。
8.权利要求1或2所述的2,4-咪唑啉二酮杂环衍生物,其特征在于:当Y1为N或S,Y2和Y3为C,Y4为N时,其结构如式Ⅵ所示:
其中,X1、X2独立地为O或S;R1为-H、C1~C4烷基、R2、R3独立地为-H、C1~C4烷基、卤素、C1~C4烷氧基或n=1~4的整数;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;R5为-COOH、苯基、C3~C8环烷基或卤素;
优选的,X1、X2独立地为O或S;R1为-H或R2、R3独立地为-H或C1~C4烷基;R4为-H、C1~C4烷基、卤素、C1~C4烷氧基、-CF3、-NH2或-OH;
进一步优选的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H或C1~C4烷基;
最优的,X1、X2独立地为O或S;R1为-H;R2、R3独立地为-H。
9.2,4-咪唑啉二酮杂环衍生物,其结构式为:
10.权利要求1~9任一项所述2,4-咪唑啉二酮杂环衍生物药学上可接受的盐或水合物。
11.一种药物组合物,是由权利要求1~9任一项所述的2,4-咪唑啉二酮杂环衍生物、权利要求10所述的盐或水合物添加药学上可以接受的辅助性成分制备而成的。
12.权利要求1~9任一项所述的2,4-咪唑啉二酮杂环衍生物、权利要求10所述的盐或水合物在制备Pim-1蛋白激酶小分子抑制剂中的用途。
13.权利要求1~9任一项所述的2,4-咪唑啉二酮杂环衍生物、权利要求10所述的盐或水合物在制备抗肿瘤药物中的用途。
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CN114945569A (zh) * | 2019-12-26 | 2022-08-26 | 延世大学校产学协力团 | 吡咯烷衍生物,以及包含其的用于预防或治疗β-淀粉样蛋白或Tau蛋白相关疾病的药物组合物 |
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CN114945569A (zh) * | 2019-12-26 | 2022-08-26 | 延世大学校产学协力团 | 吡咯烷衍生物,以及包含其的用于预防或治疗β-淀粉样蛋白或Tau蛋白相关疾病的药物组合物 |
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